Cryptococcus neoformans meningitis occurs in approximately 225,000 individuals with AIDS each year, resulting in over 181,000 annual deaths. C. neoformans is an opportunisitic fungal pathogen that is inhaled and subsequently escapes the lungs and disseminates to the central nervous system where life-threatening meningitis occurs. Host factors that determine whether C. neoformans initially survives or is destroyed by pulmonary phagocytes remain poorly defined, presenting a major gap in understanding how this pathogen ultimately causes meningitis and death. It is postulated that C. neoformans uses macrophages for transport from the lung to the brain to cause meningitis. However, C. neoformans can be killed in some macrophages but replicates in others. In addition, we and others have shown that dendritic cells (DCs), a critical innate phagocyte in the lung, can engulf and destroy C. neoformans, but like macrophages this may be restricted to a subset of DCs. Our preliminary data indicate subsets of primary human pulmonary macrophages and DCs interact with C. neoformans and exhibit differential anti-cyptococcal activities. Some innate phagocyte subsets kill C. neoformans, and others do not. Therefore, we hypothesize that subsets of innate phagocytes in the lung are capable of restricting C. neoformans growth through direct intracellular fungicidal activity absent in permissive subsets of DCs and macrophages. We will monitor and characterize the fungicidal response of human pulmonary phagocyte subsets to C. neoformans and then examine roles of mediators of fungicidal activity (iNOS, ROS, and lysosomal enzyme cathepsin B) in each subset (Aim 1). Next, we will identify differentially regulated genes and signaling pathways that may coordinate fungicidal activity in each subset following interaction with C. neoformans (Aim 2). Consequently, our studies will identify phagocyte subsets responsible for anti-cryptocccal activity or permissive fungal growth and identify the host genes and signaling pathways that may be responsible for regulating these responses.